Trichloroethylene and its metabolite TaClo lead to degeneration of substantia nigra dopaminergic neurones: Effects in wild type and human A30P mutant α-synuclein mice.

Parkinson's disease (PD) is characterised pathologically by degeneration of the dopaminergic (DA) neurones of the substantia nigra pars compacta (SNpc) and the presence of α-synuclein containing Lewy body inclusions. Trichloroethylene (TCE) has been suggested as a potential environmental chemical that may contribute to the development of PD, via conversion to the neurotoxin, 1-Trichloromethyl-1,2,3,4-tetrahydro-ß-carboline (TaClo). We investigated the effect of an 8 week exposure to TCE or TaClo on wild type and, as an experimental model of PD, A30P mutant α-synuclein overexpressing mice using a combination of behaviour and pathology. TCE or TaClo exposure caused significant DA neuronal loss within the SNpc in both wild type and transgenic mice. Cell numbers were lower in A30P animals than wild type, however, no additive effect of TCE or TaClo exposure and A30P overexpression was found. TCE or TaClo did not appear to lead to acceleration of motor or cognitive deficits in either wild type or A30P mutant mice, potentially because of the modest reductions of DA neuronal number in the SNpc. Our results do however suggest that TCE exposure could be a possible factor in development of PD like changes following exposure.

Diquat causes caspase-independent cell death in SH-SY5Y cells by production of ROS independently of mitochondria.

Evidence indicates that Parkinson's disease (PD), in addition to having a genetic aetiology, has an environmental component that contributes to disease onset and progression. The exact nature of any environmental agent contributing to PD is unknown in most cases. Given its similarity to paraquat, an agrochemical removed from registration in the EU for its suspected potential to cause PD, we have investigated the in vitro capacity of the related herbicide Diquat to cause PD-like cell death. Diquat showed greater toxicity towards SH-SY5Y neuroblastoma cells and human midbrain neural cells than paraquat and also MPTP, which was independent of dopamine transporter-mediated uptake. Diquat caused cell death independently of caspase activation, potentially via RIP1 kinase, with only a minor contribution from apoptosis, which was accompanied by enhanced reactive oxygen species production in the absence of major inhibition of complex I of the mitochondrial respiratory chain. No changes in α-synuclein expression were observed following 24-h or 4-week exposure. Diquat may, therefore, kill neural tissue by programmed necrosis rather than apoptosis, reflecting the pathological changes seen following high-level exposure, although its ability to promote PD is unclear.

Histological and angiographic effects of a pulsed holmium:YAG laser in normal and atherosclerotic human coronary arteries and aorta.

OBJECTIVE: The aims were (1) To determine the histological and angiographic effects of holmium:YAG laser energy delivered through clinical multifibre laser catheters on fresh cadaveric coronary arteries; and (2) to relate the placement of optical fibres in the catheter to patterns of tissue ablation in cadaveric aorta. METHODS: Eight fresh cadaveric hearts and segments of aorta were used. Hearts were mounted on a new pressure perfusion device. The laser catheter was delivered over a guidewire in the lumen until it met an area of resistance. The coronary artery lumen was perfused at approximately 100 mm Hg mean pressure. These arterial areas were identified on angiography, marked, and then exposed to laser energy in the range 600-3000 mJ.mm-2. Normal and atherosclerotic areas of fresh cadaveric aortic strips were exposed to increasing laser energies using either constant or increasing fluence. Coronary arteries were pressure perfused with formalin for 18-24 h at 100 mm Hg mean pressure, and aortic strips were immersed in 5% formalin. Light and scanning electron microscopy studies were carried out. RESULTS: There were no perforations or dissections by angiography in the fresh coronary arteries. One of 15 normal coronary artery segments and 10 of 16 of the pressure perfused, fixed, atherosclerotic coronary artery segments showed thermal changes associated with atherosclerotic plaque ablation. In aortic tissue, thermal effects extended 0 to 0.6 mm lateral to the ablated crater. Acoustic effects were seen only in the aortic strips after ablation at fluences > 1000 mJ.mm-2. The "dead spaces" around the optical fibres in the catheter resulted in significant amounts of coagulated tissue fragments remaining in the crater. CONCLUSIONS: Holmium:YAG laser energy delivered through multifibre catheters ablated atherosclerotic tissue in coronary arteries with minimal damage to the normal walls. The cadaveric coronary artery perfusion apparatus is useful for assessing catheter delivery and mobility and the effects of laser energy on the coaxially orientated normal and atherosclerotic coronary arterial wall.